Preparation of amino acid derivatives

ABSTRACT

Amino acid derivatives are prepared by reacting a 2,4 or 4 substituted-4H-oxazol-5-one with a carboxylic acid halide to form a novel oxazole product which rearranges on heating to the azlactone which is also novel. The rearranged product is reacted with ammonia, an alcohol, a mercaptan or amines to form the corresponding amino acid derivatives which are useful as pharmaceutical intermediates.

United States Patent 91 Pives [54] PREPARATION OF AMINO ACID DERIVATIVES[75] lnventor: Seemon H. Pives, Murray Hill, NJ.

[73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: June 5, 1970 21 Appl. No.1 57,395

Related U.S. Application Data [62] Division of Ser. No. 774,213, Nov. 7,1968, Pat. No.

[52] U.S. Cl. ..260/47l A, 260/455 R, 260/559 D [51] Int. Cl ..C07c103/30 [58] Field of Search ..260/455 R,

471 A, 558 S, 558 A, 559 D 51 Feb. 13,1973

[56] References Cited OTHER PUBLlCATlONS Finar, l. L., OrganicChemistry, Vol. 1, Pub. By R. Clay and Co., Inc. Great Britain, page 677cited.

Primary Examiner-Lorraine A. Weinberger Assistant Examiner-L. ArnoldThaxton Att0rneyl. Louis Wolk, Harry E. Westlake, Jr. and Francis H.Deef 57 ABSTRACT 8 Claims, No Drawings PREPARATION OF AMINO ACIDDERIVATIVES This application is a division of U.S. S er. No. 774,213filed Nov. 7, 1968 now Pat. No. 3,676,453."

It is known in the art that-various amino acid derivatives, such as thevarious derivatives of alanine and serine, are useful in thepharmaceutical fields. See. U.S. Pat. Nos. 2,868,818, No. 3,344,023, No.3,275,648 and Journal of Organic Chemistry, volume 33, pages 1758-1761(1968 In general, the synthesis of such compounds is relatively complexand requires a number of different reaction steps. It is an object ofthe present invention to provide a different reaction procedure forforming such amino acid derivatives. A further object is to provide anovel and useful class of compounds which are useful pharmaceuticalintermediates. Other objects will become apparent as the description ofthe invention proceeds.

These objects are accomplished by the present invention which provides aprocess for preparing a compound of the formula 6 R: (I) Rr-iil-- RB l iNH- Rr wherein R is an aromatic radical containing from six to about 25carbon atoms;

R is a lower alkyl group from one to about five carbon atoms;

R is selected from the group consisting of OR,

Nl-l NI-lR and N-R wherein each of the Rs are organic radicalscontaining from one to about carbon atoms;

R is selected from the group consisting of H, an aromatic radical bondedthrough a nuclear carbon atom and a halogenated methyl group;

Which comprises (A) reacting, in an inert solvent, an aromaticcarboxylic acid halide containing from seven to about 26 carbon atomswith a compound of the formula (B) heating the product which rearrangesto form and then (C) reacting the rearranged product with a compoundselected from the group consisting of ROH, RSI-l, Nl-l RNH, and

R-Nll wherein the Rs are defined above.

The present invention also provides a process for preparing compounds ofthe formula wherein R, is an aromatic radical containing from six toabout 25 carbon atoms;

R is a lower alkyl group of from one to about five carbon atoms;

R;, is selected from the group consisting of OR,

--NH Nl-IR and wherein each of the Rs are organic radicals containingfrom one to about l0 carbon atoms;

R, is selected from the group consisting of B, an aromatic radicalbonded through a nuclear carbon atom and a halogenated methyl group;

which comprises reacting a compound of the formula with a compoundselected from the group consisting of ROH, RSI-l, NH RNH and R-NH,wherein the Rs are defined above.

The present invention further provides a compound selected from thegroup consisting of R, is an aromatic containing from six to about 25carbon atoms;

R is a lower alkyl group of from one to about five carbon atoms; and

R, is selected from the group consisting of H, an'aromatic radicalbonded through a nuclear carbon atom and a halogenated methyl group.

The radicals" referred to above are defined in terms of the number ofcarbon atoms but it is to be understood that such radicals may containfunctional groups such as amino groups,carboxyl groups, hydroxyl groupsand the like. The expression "aromatic radical bonded through a nuclearcarbon atom means that the radical is attached by a bond from a carbonatom in the ring. The terminology halogenated methyl group means aradical of the formula wherein each of the Xs are halogen or hydrogen.Any

inert solvent may be used for the reactions providing they at leastpartially dissolve the reactants and do not react with the reactants.

The reaction sequence is given below:

in carrying out reaction (1) above, various aromatic carboxylic acidhalides may be used. Among them are included benzyl chloride,dibenzyloxybenzoyl chloride, p-chlorobenzoyl chloride, p-methoxybenzoylchloride, 3,4-dimethoxybenzoyl chloride and the like. Halides other thanthe chlorides may also be used. The reaction is preferably carried outin the presence of a base. While an organic base such as triethylamine,pyridine, a-picoline or the like is generally preferred, inorganic basesmay also be employed. The reaction is carried out in the presence of aninert solvent such as tetrahydrofuran, chloroform, dioxane, or any othersolvent which at least partially dissolves the reactants without takingpart in the reaction. The reaction proceeds at low temperatures and atemperature of from C. to about room temperature is generally employed.However, the reaction may be carried out at a lower temperature for alonger period of time or it may be carried out at a high temperatureunder pressure if the solvent or reactants are volatile. The temperaturetherefore is not critical and may be selected as desired.

The arrangement reaction (2) give above is merely carried out by heatingthe reactants in an inert solvent. Preferably the solvent is basic,i.e., triethylamine and more preferably in a pyridine compound such aspyridine itself, a-picoline, S-ethyl -Z-methyl pyridine, 2,6-lutidine,B-picoline and the like. Again the reaction has a time temperaturerelationship and temperatures approximating room temperature require anextended period'of time for the rearrangement. To hasten the reaction itis preferred that the mixture be heated from about 40 to about 100 C. sothat the rearrangement occurs within a few hours.

in carrying out reaction (3) above, the 'azlactone is highly reactiveand only mild conditions (i.e., room temperature or slight heating) arerequired to form the esters, amides and thio compounds. Again a solventis employed as the reaction medium but it is to be noted that thealcohol or other reactant itself may serve as solvent in the system.

In carrying out each of the above reactions, it is preferred that R, isphenyl, R is methyl, R is OR and R, is a substituted phenyl such as3,4-dibenzyloxyphenyl.

The following examples are given to illustrate the invention and are notintended to limit it in any manner. All parts are given in parts byweight unless otherwise expressed.

EXAMPLE 1 A. Preparation of 5-(3,4-dibenzyloxybenzoyloxy)-4-methyl-Z-phenyloxazole 3 Grams (17.1 millimoles) of N-benzoylalanineazlactone is dissolved in 10 ml. of tetrahydrofuran. To the solution isadded 1.75 g. (17.3 millimoles) of triethylamine followed by a solutionof 6.2 g. (17.5 millimoles) of 3,4-dibenzyloxybenzoyl chloride in 25 ml.of tetrahydrofuran over a 15-minute period while the temperature ismaintained at 0-10 C. After stirring for one hour, the solids areremoved by filtration and the filtrate is evaporated to leave a residueof S-(3,4- dibenzyloxybenzoyloxy)-4-methyl-2-phenyloxazole. The productis recrystallized from 20 ml. ethyl alcohol to give a 65% yield ofproduct having a melting point of l0l-l03 C. It can also berecrystallized from ether and ethyl acetate. The product is identifiedby N.M.R., LR. and elemental analysis.

B. Preparation of 4-(3,4-dibenzyloxybenzoyl)-4-methyl-2-phenyloxazole-5-one To 1 gram of the oxazole of Example 1A,above is added 5 ml. of pyridine. The mixture is heated on a steam bathfor 3 hours and then the solvent is removed in vacuo to give 1 gram of4-(3,4-dibenzyloxybenzoyl)- 4-methyl-2phenyloxazole-5-one. The productis identified by N.M.R. and [.R.

C. Preparation of benzyl dibenzyloxybenzoyl)-alaninate The product ofExample 18, is dissolved in 5 ml. of benzyl alcohol which is allowed tostand overnight. The benzyl alcohol is removed by vacuum distillationand the product is chromatographed (with chloroform) on silica gel togive benzyl N-benzoyl-2-(3,4-dibenzyloxybenzoyl)- alaninate which is asolid melting at about room temperature. The product is identified byN.M.R., [.R. and conversion to known products.

The product can be reduced and each isomer, after separation, convertedto the corresponding known serine derivative according to the proceduregiven in Journal of Organic Chemistry," Volume 33, page 1758 (1968).

EXAMPLE 2 A. Preparation of 5-benzoyloxy-4-methyl-Z-phenyloxazole Amixture of 7.72 g. (40 millimoles) of N- benzoylalanine in 40 ml. ofdioxane is warmed to near solution and then cooled to room temperature.To the mixture is added a solution of 8.26 g. (40 millimoles)dicyclohexylcarbodiimide in ml of dioxane. After one hour at roomtemperature, 4.04 g. (40 millimoles) of triethylamine is added followedby the dropwise addition of 5.62 g. (40 millimoles) of benzoyl chloride.The mixture is stirred for one hour and then filtered. The filtrate isevaporated and the residue recrystallized from ethyl alcohol to give5-benzoyloxy-4-methyl-2- phenyloxazole having a melting point of ll5-l18 C. The product is identified by N.M.R., LR. and elemental analysis.

B. Preparation of 4-benzoyl-4-methyl-2-phenyloxazol-5-one To 1 g. of theoxazole of Example 2A, above is added 5 ml. of a-picoline. The mixtureis heated on a steam bath for 3 hours and then the solvent is removed invacuo to give l g. of 4-benzoyl-4-methyl-Z-phenyloxazol-S-one. Theproduct is identified by N.M.R. and LR.

C. Preparation benzoylalaninate The product of Example 28, is dissolvedin 5 ml. of methyl alcohol which is allowed to stand overnight. Themethyl alcohol is removed by vacuum distillation nd the product ischromatographed (with chloroform) on silica gel to give methylN-benzoyl-2- benzoylalaninate. The product is identified by N.M.R. andLR.

of methyl N-benzoyl-2- EXAMPLE 3 A. Preparation of5-p-chlorobenzoyloxy-4-methyl-2- phenyloxazole The procedure of Example2A, is repeated with the substitution of 7 g. (40 millimoles) ofp-chlorobenzoyl chloride for the benzoyl chloride. The product is5-pchlorobenzoyloxy-4methyl-2-phenyloxazole having a melting point ofl27l 29 C.

B. Preparation of 4-p-chlorobenzoyl-4-methyl-2- phenyloxazol-S-one Theprocedure of Example 13, is repeated employing the oxazole of Example3A, above. The resulting product is4-p-chlorobenzoyl-4-methyl-2-phenyloxazole-S-one which is identified byN.M.R. and LR.

C. Preparation of methyl N- benzoyl-Z-pchlorobenzoyl alaninate A slurryof l g. of 4-p-chlorobenzoyl-4-methyl-2- phenyloxazol-S-one in 10 ml. ofmethanol is stirred for 16 hours at room temperature. The excessmethanol is removed by vacuum distillation to give a residue of methylN-benzoyl-Z-p-chlorobenzoyl alaninate. The product is identified byN.M.R. and LR.

EXAMPLE4 A. Preparation of 5-(m-methoxybenzoyloxy)-4-methyl-Z-phenyloxazole The procedure of Example 1A, is repeated with thefollowing changes. Instead of the addition of dibenzyloxybenzoylchloride there is added the acid chloride formed as follows: A solutionof 2.6 g. 17 millimoles) of m-methoxybenzoic acid in 5 cc. of thionylchloride is refluxed for 4 hours. The solvent is removed in vacuo andthe residue dissolved in 25 ml. of tetrahydrofuran. The solution is thenused in the procedure of Example 1A. The resulting product is 5-(m-methoxybenzoyloxy)-4-methyl-2-phenyloxazole. The product isidentified by N.M.R. and LR.

B. Preparation of 4-m-methoxybenzoyl-4-methyl-2- phenyloxazole-S-one Theprocedure of Example 113, is repeated employing the oxazole of Example4A. The resulting product is4-m-methoxybenzoyl-4-methyl-2-phenyloxazole-5-one which is identified byN.M.R. and LR.

C. Preparation of benzyl N-benzoyl-2-m-methoxybenzoyl alaninate Theprocedure of Example 1C. is repeated employing the compound of Example43. The resulting product is benzyl N-benzoyl-2-m-methoxybenzoylalaninate which is identified by N.M.R. and LR.

EXAMPLE 5 A. Preparation of 5-benzyloxy-4-iso-butyloxazole 6.36 Grams(40 millimoles) of N-formylleucine in 20 ml. of 1,2-dimethoxyethane isreacted with 8.26 g. (40 millimoles) of dicyclohexylcarbodiimide. Thesolids are filtered after 2 hours and 4.04 g. (40 millimoles) ofN-methyl morpholine is added followed by the dropwise addition of 5.62g. (40 millimoles) of benzoyl chloride. The resulting product isisolated according to Example 2A, and is 5-benzoyloxy-4-isobutyloxazole.

B. Preparation of 4-benzoyl-4-isobutyloxazol-5-one The procedure ofExample 28, is employed utilizing the product of Example 5A. to give4-benzoyl-4-isobutyloxazol-S-one. The product is identified by N.M.R.and LR.

C. preparation of the ester The procedure of Example 1C. is repeatedemploying the compound of Example 58. to form the corresponding ester.

EXAMPLE 6 A. Preparation of 5-(3,4-dibenzyloxybenzoyloxy)-4-methyl-2-trifluoromethyloxazole The procedure of Example 1A. is repeatedemploying 2.86 g. of N-trifluoroacetylalanine azlactone instead ofN-benzoylalanine azlactone. The product is 5- (3,4-dibenzyloxybenzoyloxy)-4-methyl-2- trifluoromethyloxazole.

B. Preparation of 4-(3,4-dibenzyloxybenzoyl)-4-methyl-2-trifluoromethyloxazol-5-one The procedure of Example 1B, isrepeated employing the product of Example 6A. The resulting product is4-(3,4-dibenzyloxybenzoyl)-4-methyl-2- trifluoromethyloxazol-S-one whichis identified by N.M.R. and LR.

C. Preparation of the ester The procedure of Example 1C, is repeatedemploying the product of Example 6B, to obtain the corresponding ester.

EXAMPLE 7 A. Preparation of 5-benzoyloxy-4-methyl-2-pnitrophenyloxazoleThe procedure of Example 2A, is repeated employing 9.5 g. (40millimoles) of N-p-nitrobenzoylalanine instead of N-benzoylalanine. Theresulting product is 5- benzoyloxy-4-methyl-2-p-nitrophenyloxazole whichis identified by N.M.R. and LR.

B. Preparation of 4-benzoyl-4-methyI-Z-p-nitrophenyloxazol-S-one Theprocedure of Example 13. is repeated employing the product of Example7A. The resulting product is4-benzoyl-4-methyl-2-p-nitrophenyloxazol-5-one which is identified byN.M.R. and LR.

C. Preparation of the ester The procedure of Example 1C, is carried outemploying the product of Example 78 to obtain the corresponding esterwhich is identified by N.M.R. and LR.

EXAMPLE 8 A. Preparation of the N-methylamide of N-benzoyl-2-benzoylalanine 4-Benzoyl-4-methyl-2-phenyloxazol-5-one is preparedaccording to the procedure of Example 213 given above. A solution of4-benzoyl-4-methyl-Z-phenyloxazol-S-one in tetrahydrofuran is treatedwith a 2 molar excess of methylamine in the same solvent. When the ir ofthe solution shows the absence of the absorption at ca. 1,825 cm., thevolatiles are removed leaving the N-methylamide of N-benzoyl-Z-benzoylalanine.

EXAMPLE9 A. Preparation of butyl 2-benzamido-2- benzoylthiopropionate4-Benzoyl-4-methyl-2-phenyloxazol-5-one is prepared according to theprocedure of Example 23, given above, 1 Gram of4-benzoyl-4-methyl-2-phenyloxazol-S-one is dissolved in IQ ml. ofdioxane. A 0.5 molar excess of butyl mercaptan is added to the solutionand the mixture is allowed to stand overnight. The volatiles are removedleaving butyl 2-benzamido-2- benzoylthiopropionate.

EXAMPLE 10 A. Preparation of N-dibenzylamide of n-benzoyl2benzoylalanine The procedure of Example 8A, is repeated employingdibenzylamine rather than methylamine. The resulting product is thecorresponding N-dibenzylarnide of n-benzoyl-Z-benzoylalanine.

EXAMPLE 1 l A. Preparation of the amide of N-benzoyl-2- benzoylalanineThe procedure of Example 8A. is repeated employing ammonia rather thanmethylamine. The resulting product is the amide ofN-benzoyl-2-benzoylaianine.

While in the above examples, a limited number of reactants, solvents,temperatures and the like are given, it is obvious that other reactants,solvents and temperatures can be employed with equally successfulresults.

Many other equivalent modifications would be apparent to those skilledin the art from a reading of the foregoing without a departure from theinventive concept.

What is claimed is:

l. A process for preparing a compound of the formula wherein R isdibenzyloxyphenyl; R is a lower alkyl group;

R is selected from the group consisting of OR,

SR, NH,, NHR and AFR wherein each of the Rs are hydrocarbon radicals containing from one to seven carbon atoms;

R, is selected from the group consisting of phenyl and trifluoromethyl;I which comprises (A) reacting, in an inert solvent,

(B) heatingthe product to a temperature of from 40C. to C. whichrearranges to form ahd then (C) reacting the rearranged product withcompound selected from the group consisting of ROH, RSN, NH3, and

wherein the Rs are defined above.

2. A process for preparing compounds of the formula 0 NH%R4 wherein R isdibenzyloxyphenyl; R is a lower alkyl group; R is selected from thegroup consisting of -OR,

SR, --Nl-l -NHR and wherein each of the Rs are hydrocarbon radicalscontaining from one to seven carbon atoms;

with a compound selected from the group consisting of ROH, RSH, NH RNl-land R R-BIIH wherein the Rs are defined above.

3. The process of claim 1 wherein R. is phenyl. 4. The process of claim1 wherein R is methyl.

5. The process of claim 1 wherein R is OR.

6. The process of claim 2 wherein R is phenyl. 7. The process of claim 2wherein R is methyl.

8. The process of claim 2 wherein R is OR.

1. A process for preparing a compound of the formula wherein R1 isdibenzyloxyphenyl; R2 is a lower alkyl group; R3 is selected from thegroup consisting of -OR, -SR, -NH2, NHR and wherein each of the R''s arehydrocarbon radicals containing from one to seven carbon atoms; R4 isselected from the group consisting of phenyl and trifluoromethyl; whichcomprises (A) reacting, in an inert solvent, dibenzyloxybenzoyl halidewith a compound of the formula
 2. A process for preparing compounds ofthe formula wherein R1 is dibenzyloxyphenyl; R2 is a lower alkyl group;R3 is selected from the group consisting of -OR, -SR, -NH2, -NHR andwherein each of the R''s are hydrocarbon radicals containing from one toseven carbon atoms; R4 is selected from the group consisting of phenyland trifluoromethyl; which comprises reacting a compound of the formula3. The process of claim 1 wherein R4 is phenyl.
 4. The process of claim1 wherein R2 is methyl.
 5. The process of claim 1 wherein R3 is -OR. 6.The process of claim 2 wherein R4 is phenyl.
 7. The process of claim 2wherein R2 is methyl.